First missense mutations (R388W and R425H) of AMPD1 accompanied with myopathy found in a Japanese patient

Skeletal muscle AMP deaminase (AMPD: E.C. 3.5.4.6) deficiency is one of the most common inherited defects in the Caucasians, but not in Asians. Although a diagnosis of AMPD1 deficiency is indeed based on the reduced enzymatic activity, its clinical significance is still rather controversial since most subjects are asymptomatic. Alternative splicing of exon 2 in individuals who have inherited this defect is thought to provide a mechanism for phenotypic rescue that may explain the variability of clinical symptoms as we reported earlier. In this report we present the first case with a detectable defect of the AMPD1 gene in a Japanese patient with myopathy. Two missense mutations (R388W and R425H) in exon 9 and exon 10 of the AMPD1 gene were found. Prokaryotic expression showed a comparable amount of the AMPD1 peptides and undetectable AMPD activity in the constructs with these mutations. From this study, we have concluded that this patient is a compound heterozygote for AMPD1 mutant allele. This study also demonstrates the first reported instance of detectable dysfunction of the AMPD1 gene product, suggesting that AMPD1 indeed has a key role in muscle metabolism and function. Hum Mutat 16:467–472, 2000. © 2000 Wiley-Liss, Inc.